This message is in MIME format. If you are reading this text, then your mail package doesn't fully support MIME - there may be a newer release available from your supplier. Created using the !Marcel mail package from ANT Ltd <[log in to unmask]> --80-1904222667-850909220:#-1543471909 Content-Type: TEXT/PLAIN; CHARSET=ISO-8859-1 Hello All, The attached charts and text need to be read together. If I have overloaded anyone's system, please accept my apologies. (You also need to be able to handle picture files in GIF format). The charts provide a plausible (and I hope reasonable) explanation of why it becomes progressively more difficult to manage our PD using levodopa tablets, and also explain how the effective duration of each tablet can be affected by the severity of PD. For Jon Meyer: You may like to know that it was trying to explain your unusual results that led me to this theory, so you never know when that last piece of the jigsaw will click into place. I would welcome any comment on the charts; the way I see it, if I can convince you sceptics, I can convince anyone! -- Brian Collins <[log in to unmask]> --80-1904222667-850909220:#-1543471909 Content-Type: IMAGE/GIF; NAME=ChartA Content-Transfer-Encoding: BASE64 R0lGODdhDgSOAuMAAP///93d3bu7u5mZmXd3d1VVVTMzMwAAAABEme7uAADM AN0AAO7uu1WIAP+7AAC7/ywAAAAADgSOAgAE/hDISau9OOvNu/9gKI5kaZ5o qq5s675wLM90bd94ru987//AoHBILBqPyKRyyWw6n9CodEqtWq/YrHbL7Xq/ 4LB4TC6bz+i0es1uu9/wuHxOr9vv+Lx+z+/7/4CBgoOEhYaHiGcFi4yNjo+Q kZKTlJWWl5iZmpucnZ6foKGio6SlpqeoqaqrrK2ur7CxsrOYhwIHuLm6u7y9 vr/AwcLDxMXGx8jJysvMzc7P0NHS09TV1tfY2drb3N3e3+DFAgKF4ebn6Onq 6+zt7u/w8fLz9PXw5fb5+vv8/f7/AAMKHEhQH76CCBMqXMiwocOHECPmOyix osWLGDNq3Mix4zWK/gNCihxJsqTJkyhTqlzJsqXLlzBjypxJs6bNmzhz6tzJ s6fPn0CDCh1KtKjRo0iTotxFMYDTp1CjSp1KtarVq1izat3KtavXr2DDih1L tqzZs2jTql3Ltq3bt3Djyp1Lt67dqkwJ6brLt6/fv4ADCx5MuLDhw4gTK17c N++gvYwjS55MubLly5gza97MubBjQZA7ix5NurTp06hTq15N+HOg0Kxjy55N u7bt27hzk3UNCLbu38CDCx9OvLhxs7z/+H46rrlzqc2nRrcqIOR0qM6zC7h6 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II3XeidwdlFxTlWzbMmWCPvxCeXVX2VyHCPhYQv3etOXc2v2ZFmCFycyEWRW FKPwZgf1ZWswemXCZONCZdXXf8nSahWyarNgav/XgA8YgRNYgReYgRvYgR8Y giNYgieYgivYgi8YgzNYgzeYgzvYgz8YhENYhEeYhEvYhE8YhVNYhVeYhVvY hV8YhmNYhmeYhmvYhmE3AgAAOw== --80-1904222667-850909220:#-1543471909 Content-Type: TEXT/Plain; NAME=TextA Content-Transfer-Encoding: QUOTED-PRINTABLE THE INTERACTION OF LEVODOPA AND PARKINSON'S DISEASE 1) The system for producing the neuro transmitter Dopamine can be=20 considered as a manufacturing unit. It is geared up to sypply the system which carries the messages from the brain to the muscles, and must at all times supply precisely AS MUCH as is needed, WHERE it is needed, WHEN it is needed. The actual production takes place in the Substantia Nigra. =20 2) Studies carried out at the University of Nottingham and elsewhere have established that people who do not have Parkinson's Disease do not=20 suffer a loss of Dopamine production capacity with increasing age: The commonly-held picture of the entire population losing Dopamine production=20 capacity, with the unlucky ones whose capacity drops below the 10% to 20% level developing PD is wrong. The picture is one where the majority of the population live their lives without significant loss of capacity, while the PWP (perhaps from birth) go steadily downhill. =20 3) An interesting side-issue stemming from this picture is that there are about twice the number of identified PWPs i.e. (240,000 people in the UK, 1 million to 3 million in the USA - depending whose stastics you use) walking around in blissful ignorance that their personal clock has=20 started ticking, and one day they will become a PWP. =20 4) It is established that the onset of tremor, which is the usual but not invariable first symptom of PD, occurs when 80% to 90% of the Dopamine- producng cells have ceased to function. In the chart, I have used 90% loss: It does not affect the argument. =20 5) When a person develops PD symptoms, we assume that his remaining 10% of Substantia Nigra (SN) cells are working flat out and just failing to=20 meet the demand. The addition of a little levodopa puts everything right for the time being.=20 =20 6) The PWP at this point can tolerate quite large doses of levodopa, because his control system can shut down the full 10% of flow to counteract the invading tablet's contents. =20 7) Note that for convenience I will refer to "10% of flow" when I should=20 really say "The Dopamine flow corresponding to 10% of SN cells". =20 8) When the first symptom makes itself known, we know the critical 10% of flow number. It would seem reasonable to assume that this 'magic=20 number' was the target for stable operation before the onset of symptoms, and will continue to be in the future. So the problem facing the PWP=20 is: How to maintain a steady 10%of flow. =20 9) Counting years from onset of symptoms, the SN production capacity=20 continues to deteriorate, and the PWP must balance this with Dopamine from tablets. With such a crude tool to do the job it is no wonder that we have problems. 10) Consider what happens after 5 years (Remember this is a hypothetical model, not someone's actual experience. Since I have already seen 17 years since diagnosis, and 23 years since first symptoms I can=20 guarantee that it is not based on me!) At 5 years, the SN can only=20 make 3% of flow. Starting from the zero flow line, suppose we gradually=20 raise the tablet-supplied dopamine flow: nothing happens until the tablet flow ( Y ) reaches 7% Together with the SN-supplied 3% : stability is=20 achieved. =20 11) If we continue to increase the tablet flow, the system will start to=20 back off its 3% of flow, to keep the total=A0at 10%. However, when its=20 output reaches zero, and the tablet contribution exceeds 10% of flow. the overdose symptoms then set in.=20 =20 12) Thus a window of X% of flow exists for us to aim at. If we miss, the over-dosed symptoms or the underdosed symptoms will result, and as X=20 grows smaller, the difficulty becomes greater. =20 13) Note that this apparent rejection of the levodopa with the diminishing window size ocurrs purely because of the progress of PD, and requires no other malfunction of the brain's system. =20 14)As the SN degrades further with time, so the value of X decreases, and Y increases, until one day the lines converge. =20 It must be remembered that this case grossly simplifies the situation, and all the values quoted are simply for the sake of the argument. Brian Collins, 15 Oct 1996 --80-1904222667-850909220:#-1543471909 Content-Type: TEXT/Plain; NAME=TextB Content-Transfer-Encoding: QUOTED-PRINTABLE HOW PARKINSON'S DISEASE AFFECTS THE DURATION OF EFFECTIVENESS OF TABLETS. I was thinking recently about the bits of information which I had gathered along the way, which seemed to indicate that newly-diagnosed PWPs seemed to get a significantly longer duration of effectiveness out of each levadopa- based tablet, compared with old hands like myself. I ruled out a theory involving different rates of digestion affecting the concentration of=20 levodopa in the bloodstream a) because the effect would be measurable and=20 there are no reports correlating years since onset with levels of levodopa in the blood stream, and b) because I did not see why age should cause the speed of digestion to vary so progressively. I now realise that the answer was already available from my chart which I produced to show how our sensitivity to levodopa increases with time as a result of our continuing loss of SN (Substantia Nigra) cells and not to do with any 'burn-out' due to excessive use of levodopa. The story is thus: Referring to chart A 1) If we consider two PWPs, PWP1 at 1 year from onset of symptoms, and PWP2 at 10 years from onset of symptoms, Chart A shows the remaining effective SN cells to be 8% and 1% respectively. 2) As described in the text accompanying Chart A, this means that PWP1 can tolerate variations in flow (from tablets) ranging from 2% to 10% flow without showing symptoms of overdose or underdose, whereas PWP2 can only tolerate variations between 9% and 10%. 3) Chart B shows the hypothetical effect of a tablet (or what's left of it) arriving at the SN, and the resultant Dopamine level in th SN. All sorts of shape for this envelope can be played with, but essentially it boils down to a fairly flat bit in the middle, with a build-up at the start, and a decay at the end. (It doesn't have to be symmetrical). 4) It is now easy to see that PWP1 will 'switch on' as soon as the tablet- induced flow exceeds 2%, and as this supposed tablet peaks-out at just about 10%, PWP1 will not show overdose symptoms, and will feel fine for a total of 5 hours. until the flow again drops below the 2% level. 5) PWP2, taking the same tablet, will a) appear to wait ages before any- thing happens, and then will only see an effective relief of symptoms for a total of 2 hours. Thus the same tablet can appear to be effective=20 for periods ranging from 2hrs to 5hrs, depending on the level of PD in the patient. --80-1904222667-850909220:#-1543471909--